Major depression is a serious health problem affecting more than 5% of the population, with a life-time prevalence of 15-20%.
Selective serotonin reuptake inhibitors have produced significant success in treating depression and related illnesses and have become among the most prescribed drugs. They nonetheless have a slow onset of action, often taking several weeks to produce their full therapeutic effect. Furthermore, they are effective in fewer than two-thirds of patients.
Serotonin selective reuptake inhibitors (SSRIs) are well known for the treatment of depression and other conditions. SSRIs work by blocking the neuronal reuptake of serotonin, thereby increasing the concentration of serotonin in the synaptic space, and thus increasing the activation of postsynaptic serotonin receptors.
However, although a single dose of an SSRI can inhibit the neuronal serotonin transporter which would be expected to increase synaptic serotonin, long-term treatment is required before clinical improvement is achieved.
It has been suggested that the SSRIs increase the serotonin levels in the vicinity of the serotonergic cell bodies and that the excess serotonin activates somatodendritic autoreceptors, 5-HT1A receptors, causing a decrease in serotonin release in major forebrain areas. This negative feedback limits the increment of synaptic serotonin that can be induced by antidepressants.
A 5-HT1A antagonist would limit the negative feedback and should improve the efficacy of the serotonin reuptake mechanism. (Perez, V., et al., The Lancet, 349:1594-1597 (1997)). Such a combination therapy would be expected to speed up the effect of the serotonin reuptake inhibitor.
Thus, it is highly desirable to provide improved compounds which both inhibit serotonin reuptake and which are antagonists of the 5-HT1A receptor.
In accordance with this invention, there is provided a group of novel compounds of the formula: 
wherein
R1, R4, R5, R6 and R8 are, independently, hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
R2 and R3, are independently; hydrogen, alkyl of 1 to 6 carbon atoms, halogen, hydroxy, cyano or amino;
R7 is hydrogen or alkyl of 1 to 6 carbon atoms;
the dotted line represents an optional double bond;
Z is CR8 or N; and
n is an integer 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.
Of these compounds, the preferred members are those in which R1 is hydrogen, hydroxy, halo, cyano, trifluoromethyl, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms. Still more preferred are compounds in which R1 is hydrogen.
In other preferred embodiments R2 is hydrogen, alkyl of one to six carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has one to six carbon atoms. Still more preferred are compounds in which R2 is hydrogen or lower alkyl.
R3 is preferably hydrogen or alkyl of one to six carbon atoms. Still more preferred are compounds in which R3 is hydrogen or lower alkyl.
In some embodiments of the present invention it is preferred that R2 and R3 are the same and are selected from hydrogen and lower alkyl.
R4, R5 and R6 are preferably independently selected from hydrogen, hydroxy, halogen, cyano, carboxamido, alkyl of one to six carbon atoms, and alkoxy of one to six carbon atoms. R4, R5 and R6 are more preferably independently selected from hydrogen and halogen.
R7 is preferably hydrogen.
When Z is CR8, then R8 is hydrogen, hydroxy, halogen, cyano, carboxamido, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms.
It is preferred in some embodiments of the invention that n is 0 or 1. Still more preferred is when n is 0.
In other preferred embodiments of the present invention R1 is hydrogen, hydroxy, halo, cyano, trifluoromethyl, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms; R2 is hydrogen, alkyl of one to six carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has one to six carbon atoms; R3 is hydrogen or alkyl of one to six carbon atoms; R4, R5 and R6 are independently selected from hydrogen, hydroxy, halo, cyano, carboxamido, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms; and n is an integer 0 or 1.
Most preferred are compounds in which R2 and R3 are the same and are hydrogen or alkyl of one to six carbon atoms, R4, R5 and R6 are independently selected from hydrogen, halogen and cyano, R7 is hydrogen, Z is CR8, R8 is preferably hydrogen, hydroxy, halo, cyano, carboxamido, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms, n is 0 and the dotted line represents a double bond.
Alkyl as used herein refers to an aliphatic hydrocarbon chain and includes straight and branched chains such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isohexyl. Lower alkyl refers to alkyl having 1 to 3 carbon atoms.
Alkanamido as used herein refers to the group Rxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 where R is an alkyl group of 1 to 5 carbon atoms.
Alkanoyloxy as used herein refers to the group Rxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94 where R is an alkyl group of 1 to 5 carbon atoms.
Alkanesulfonamido as used herein refers to the group Rxe2x80x94S(O)2xe2x80x94NHxe2x80x94 where R is an alkyl group of 1 to 6 carbon atoms.
Alkoxy as used herein refers to the group Rxe2x80x94Oxe2x80x94 where R is an alkyl group of 1 to 6 carbon atoms.
Carboxamido as used herein refers to the group xe2x80x94COxe2x80x94NH2.
Carboalkoxy as used herein refers to the group ROxe2x80x94C(xe2x95x90O)xe2x80x94 where R is an alkyl group of 1 to 5 carbon atoms.
Halogen (or halo) as used herein refers to chlorine, bromine, fluorine and iodine.
This invention relates to both the R and S stereoisomers of the amino-methyl-2,3-dihydro-1,4-dioxino[2,3-f]quinoxalines, as well as to mixtures of the R and S stereoisomers. Throughout this application, the name of the product of this invention, where the absolute configuration of the aminomethyl-2,3-dihydro-1,4-dioxino[2,3-f]quinoxalines is not indicated, is intended to embrace the individual R and S enantiomers as well as mixtures of the two. In some embodiments of the present invention the S stereoisomer is preferred.
Where a stereoisomer is preferred, it may in some embodiments be provided substantially free of the corresponding enantiomer. Thus, an enantiomer substantially free of the corresponding enantiomer refers to a compound which is isolated or separated via separation techniques or prepared free of the corresonding enantiomer. Substantially free, as used herein means that the compound is made up of a significantly greater proportion of one stereoisomer. In preferred embodiments the compound is made up of at least about 90% by weight of a preferred stereoisomer. In other embodiments of the invention, the compound is made up of at least about 99% by weight of a preferred stereoisomer. Preferred stereoisomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts or by methods described herein. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley lnterscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).
It is further recognized that tautomers of the claimed compounds may exist for instance when R2 or R3 is OH, the compounds may exist in a number of tautomeric forms. The claims in the application, either for the title compounds or intermediates are intended to embrace individual tautomers, as well as mixtures thereof.
Pharmaceutically acceptable salts are those derived from such organic and inorganic acids as: acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, benzoic, and similarly known acceptable acids.
Specific compounds of the present invention include:
2-{[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]methyl}-2,3-dihydro[1,4]dioxino[2,3-f]quinoxaline;
2-{[4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]methyl}-2,3-dihydro-[1,4]dioxino[2,3-f]quinoxaline;
2-{[4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]methyl}-8,9-dimethyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoxaline;
2-{[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]methyl}-8,9-dimethyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoxaline;
8,9-diethyl-2-{[4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]methyl}-2,3-dihydro[1,4]dioxino[2,3-f]quinoxaline; and
8,9-diethyl-2-{[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]-methyl}-2,3-dihydro[1,4]dioxino[2,3-f]quinoxaline; and pharmaceutically acceptable salts thereof.
Novel intermediates are provided in some embodiments of the invention. Said intermediates have the formula 
wherein
R1 hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
R2 and R3 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, halogen, hydroxy, cyano and amino;
X is hydroxy, halogen, alkylsulfonate of 1 to 6 carbon atoms, trifluoromethanesulfonate or benzenesulfonate, in which the benzene ring is optionally substituted with halogen, nitro, trifluoromethyl, cyano, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms.
Compounds of Formula II are particularly useful in the preparation of compounds of Formula I. Preferred examples of compounds of Formula II include:
2,3-Dihydro[1,4]dioxino[2,3-f]quinoxalin-2-ylmethyl 4-methylbenzenesulfonate;
8,9-dimethyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoxalin-2-yl]methyl 4-methylbenzenesulfonate; and
8,9-diethyl-2,3-dihydro[1,4]dioxino[2,3-f]-quinoxalin-2-ylmethyl 4-methylbenzenesulfonate.
The 2-azaheterocyclylmethyl-2,3-dihydro-1,4-dioxino[2,3-f]quinoxalines of the invention are prepared as illustrated in Schemes I-Ill. Specifically, the appropriately substituted nitroguaiacol (1) is alkylated with allyl bromide in the presence of a suitable base such as sodium hydride to produce (2) and then demethylated by a reagent such as sodium hydroxide. The resulting 4-nitro-2-allyloxyphenol (3) is then alkylated with glycidyl tosylate or an epihalohydrin in the presence of a base such as sodium hydride to produce (4) and heated in a high boiling solvent such as mesitylene or xylene to effect both rearrangement of the allyl group and cyclization of the dioxan ring. The resulting primary alcohol (5) is converted to the tosylate by reaction with p-toluenesulfonyl chloride in the presence of a tertiary amine or alternatively to a halide by reaction with carbon tetrabromide or carbon tetrachloride in combination with triphenylphosphine. The allyl side chain is then isomerized by treatment with catalytic bis-acetonitrile palladium (II) chloride in refluxing methylene 
chloride or benzene to produce (6) and cleaved to the corresponding o-nitrobenz-aldehyde by treatment with ozone followed by diisopropylethylamine or by catalytic osmium tetroxide in the presence of sodium periodate. The aldehyde is oxidized to the o-nitrobenzoic acid (8) by a suitable oxidant such as chromium trioxide (Jones"" oxidation) or sodium chlorite and the acid converted to the o-nitroaniline with diphenylphosphoryl azide (DPPA) in the presence of a tertiary base such as diisopropylethylamine. Reduction of the resulting nitroaniline to the diamine (8) with hydrogen and palladium on carbon and cyclization by treatment with the appropriate dicarbonyl compound in some high boiling solvent such as dimethyl sulfoxide gives the title compounds of Formula I.
The o-nitrobenzaldehydes and the o-nitrobenzoic acids used in the chemistry described in Scheme I may be alternatively prepared as described in Scheme II. The appropriate mono-allylated catechol (10) is elaborated with glycidyl tosylate as described above to produce (11) and rearranged in refluxing mesitylene. Cyclization to the 
benzodioxan methanol (12) is effected by treatment with sodium bicarbonate in ethanol and the alcohol is converted to the tosylate or halide as described above. After rearrangement of the double bond by treatment with catalytic bis-acetonitrile palladium (II) chloride in refluxing methylene chloride to produce (13) and cleavage with ozone or osmium tetroxide/sodium periodate as described above, the resulting aldehyde (14) is regioselectively nitrated with a combination of nitric acid and tin (IV) chloride to produce (15). Alternatively, the aldehyde may be oxidized to the corresponding benzoic acid under Jones"" conditions as described above to produce (16) and subsequently nitrated to produce the appropriate o-nitrobenzoic acid (17).
Compounds of the invention in which R2 and R3 are not identical may be prepared from assymetric dicarbonyl compounds as described above and the regioisomers separated by chromatography. They may alternatively be prepared from the o-nitroaniline described above as shown in Scheme Ill. The appropriately substituted o-nitroaniline (18) is deprotonated with a base such as sodium hydride and alkylated with a suitable xcex1-haloketone or aldehyde, or an xcex1-haloacetal or ketal to produce (19). The nitro group is then converted to an amine by hydrogenation over a catalyst such as palladium on carbon and cyclization effected with hydrochloric acid. A suitable oxidant such as dichloro-dicyanoquinone is employed to rearomatize the heterocyclic ring to produce (IIa). Substitution of an xcex1-halonitrile for the xcex1-haloketone in this process leads to compounds of the invention in which R2 is amino; sustitution of an xcex1-haloester leads to compounds in which R2 is hydroxy. This hydroxy group may be converted to a halogen using standard 
methods such as treatment with phosphoryl chloride or thionyl chloride and the halide may be used to prepare compounds of the invention in which R2 is mono- or dialkylamino or alkoxy. Replacement of the tosylate with the appropriately substituted azaheterocycle as above gives the title compounds of the invention.
The guaiacols, catechols and azaheterocycles appropriate to the above chemistry are known compounds or can be prepared by one schooled in the art. The compounds of the invention may be resolved into their enantiomers by conventional methods or, preferably, the individual enantiomers may be prepared directly by substitution of (2R)-(xe2x88x92)-glycidyl 3-nitrobenzenesulfonate or tosylate (for the S benzodioxan methanamine) or (2S)-(+)-glycidyl 3-nitrobenzene-sulfonate or tosylate (for the R enantiomer) in place of epihalohydrin or racemic glycidyl tosylate in the procedures above.
A protocol similar to that used by Cheetham et. al. (Neuropharmacol. 32:737, 1993) was used to determine the affinity of the compounds of the invention for the serotonin transporter. The compound""s ability to displace 3H-paroxetine from male rat frontal cortical membranes was determined using a Tom Tech filtration device to separate bound from free 3H-paroxetine and a Wallac 1205 Beta Plate(copyright) counter to quantitate bound radioactivity. Ki""s thus determined for standard clinical antidepressants are 1.96 nM for fluoxetine, 14.2 nM for imipramine and 67.6 nM for zimelidine. A strong correlation has been found between 3H-paroxetine binding in rat frontal cortex and 3H-serotonin uptake inhibition.
High affinity for the serotonin 5-HT1A receptor was established by testing the claimed compound""s ability to displace [3H] 8-OHDPAT (dipropylamino-tetralin) from the 5-HT1A serotonin receptor following a modification of the procedure of Hall et al., J. Neurochem. 44, 1685 (1985) which utilizes CHO cells stably transfected with human 5-HT1A receptors. The 5-HT1A affinities for the compounds of the invention are reported below as Ki""s.
Antagonist activity at 5-HT1A receptors was established by using a 35S-GTPxcex3S binding assay similar to that used by Lazareno and Birdsall (Br. J. Pharmacol. 109: 1120, 1993), in which the test compound""s ability to affect the binding of 35S-GTPxcex3S to membranes containing cloned human 5-HT1A receptors was determined. Agonists produce an increase in binding whereas antagonists produce no increase but rather reverse the effects of the standard agonist 8-OH DPAT. The test compound""s maximum inhibitory effect is represented as the Imax, while its potency is defined by the IC50.
The results of the three standard experimental test procedures described in the preceding three paragraphs were as follows:
Hence, the compounds of this invention are combined serotonin reuptake inhibitors/5-HT1A antagonists and are useful for the treatment of conditions related to or affected by the reuptake of serotonin and by the serotonin IA receptor, such as depression, (including but not limited to major depressive disorder, childhood depression and dysthymia), anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as pre-menstrual syndrome), attention deficit disorder (with and without hyperactivity), obsessive compulsive disorder (including trichotillomania), social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa, bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction (including premature ejaculation), and related illnesses. Moreover, the compounds of this invention have potent affinity for and antagonist activity at brain 5-HT1A serotonin receptors. Recent clinical trials employing drug mixtures (eg, fluoxetine and pindolol) have demonstrated a more rapid onset of antidepressant efficacy for a treatment combining SSRI activity and 5-HT1A antagonism (Blier and Bergeron, 1995; F. Artigas et. al., 1996; M. B. Tome et. al., 1997). The compounds of the invention are thus exceedingly interesting and useful for treating depressive illnesses.
Thus the present invention provides methods of treating, preventing, inhibiting or alleviating each of the maladies listed above in a mammal, preferably in a human, the methods comprising providing a pharmaceutically effective amount of a compound of this invention to the mammal in need thereof.
Also encompassed by the present invention are pharmaceutical compositions for treating or controlling disease states or conditions of the central nervous system comprising at least one compound of Formula I, mixtures thereof, and or pharmaceutical salts thereof, and a pharmaceutically acceptable carrier therefore. Such compositions are prepared in accordance with acceptable pharmaceutical procedures, such as described in Remingtons Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985). Pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and biologically acceptable.
The compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
The amount provided to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, and the state of the patient, the manner of administration, and the like. In therapeutic applications, compounds of the present invention are provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as a xe2x80x9ctherapeutically effective amount.xe2x80x9d The dosage to be used in the treatment of a specific case must be subjectively determined by the attending physician. The variables involved include the specific condition and the size, age and response pattern of the patient. Generally, a starting dose is about 5 mg per day with gradual increase in the daily dose to about 150 mg per day, to provide the desired dosage level in the human.
Provide as used herein, means either directly administering a compound or composition of the present invention, or administering a prodrug, derivative or analog which will form an equivalent amount of the active compound or substance within the body.
The present invention includes prodrugs of compounds of Formula I. xe2x80x9cProdrugxe2x80x9d, as used herein means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula I. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). xe2x80x9cDesign and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991), Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975).
The following examples illustrate the production of representative compounds of this invention.